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STUDY QUESTION Is there a possible association between prenatal phthalate exposure and late effects in teenage daughters with respect to reproductive hormone levels, uterine volume, and number of ovarian follicles? SUMMARY ANSWER Our study showed subtle associations between phthalate metabolite concentrations in maternal serum from pregnancy or cord blood and LH and insulin-like growth factor 1 (IGF-1) levels as well as uterine volume in their daughters 16 years later. WHAT IS KNOWN ALREADY Endocrine-disrupting environmental chemicals may adversely affect human reproductive health, and many societies have experienced a trend toward earlier puberty and an increasing prevalence of infertility in young couples. The scientific evidence of adverse effects of foetal exposure to a large range of chemicals, including phthalates, on male reproductive health is growing, but very few studies have explored effects on female reproduction. STUDY DESIGN, SIZE, DURATION This follow-up study included 317 teenage daughters who were part of the Copenhagen Mother–Child Cohort, a population-based longitudinal birth cohort of 1210 females born between 1997 and 2002. PARTICIPANTS/MATERIALS, SETTING, METHODS A total of 317 female participants (median age 16 years) were examined for weight, height, and menstrual pattern. A serum sample was analysed for concentrations of reproductive hormones, and trans-abdominal 3D ultrasonography was performed to obtain the number of ovarian follicles, ovarian and uterine size. Prenatal maternal serum samples were available for 115 females, and cord blood samples were available for 118 females. These were analysed for concentrations of 32 phthalate metabolites. Weighted quantile sum regression was used for modelling associations of combined prenatal phthalate exposure with the reproductive outcomes in post-menarcheal females. MAIN RESULTS AND THE ROLE OF CHANCE In bivariate correlation analyses, negative significant associations were found between several prenatal phthalate metabolite concentrations and serum hormone concentrations (testosterone, 17-OH-progesterone, and IGF-1) as well as number of ovarian follicles in puberty. Positive significant correlations were found between prenatal phthalate exposure and FSH and sex hormone-binding globulin concentrations. Combined analyses of phthalate exposure (weighted quantile sums) showed significant negative associations with IGF-1 concentration and uterine volume as well as a significant positive association with LH concentration. LIMITATIONS, REASONS FOR CAUTION Phthalate metabolites were measured in serum from single prenatal maternal blood samples and cord blood samples. Potential concomitant exposure to other endocrine-disrupting environmental chemicals before or after birth was not controlled for. The study population size was limited. WIDER IMPLICATIONS OF THE FINDINGS Our results support the need for further research into possible adverse effects of environmental chemicals during foetal development of the female reproductive system. STUDY FUNDING/COMPETING INTEREST(S) The work was supported by The Center on Endocrine Disruptors (CeHoS) under The Danish Environmental Protection Agency and The Ministry of Environment and Food (grant number: MST-621-00 065). No conflicts of interest are declared. TRIAL REGISTRATION NUMBER N/A. [ABSTRACT FROM AUTHOR]

Background: Burning mouth syndrome (BMS) is a chronic pain condition affecting the oral cavity. This condition mostly affects peri‐ or postmenopausal women; for this reason, sexual hormonal changes have been implicated in BMS pathogenesis. Methods: A systematic review was performed in MEDLINE/PubMed, Scopus, Web of Science, Cochrane Library and EMBASE without restriction for language or year. Eligibility criteria were controlled studies addressing the PICO question: (P) patients with BMS; (I) detection of the sex hormones; (C) patients without BMS; (O) changes on sexual hormones as a risk factor for BMS severity. Risk of bias was performed with Newcastle‐Ottawa Quality Assessment Scale. Results: Four studies were included. Salivary levels were evaluated in three studies and serum blood was used in one. Three studies analysed oestradiol and/or dehydroepiandrosterone (DHEA), two assessed progesterone and one evaluated follicle‐stimulating hormone (FSH). Oestradiol results were contradictory, with two studies reporting lower levels in BMS patients compared to controls and one finding the opposite. DHEA was statistically lower in the BMS group in one study. Progesterone showed opposite results in two studies, although none with statistical significance. FSH was statistically higher in the BMS group compared to controls. Correlation of hormones with quality of life was performed in three studies and there was no significant correlation with self‐perceived symptoms severity. Conclusion: Sexual hormones can be altered in BMS, especially oestradiol. Despite these changes, we did not find correlation between hormone fluctuation and BMS symptoms intensity affecting quality of life. These findings suggested the need for further investigation on hormonal alterations, which may be a promising target on BMS management. [ABSTRACT FROM AUTHOR]

Air pollution exposure is ranked as a leading environmental risk factor for not only cardiopulmonary diseases but also for systemic health ailments including diabetes, reproductive abnormalities, and neuropsychiatric disorders, likely mediated by central neural stress mechanisms. Current experimental evidence links many air pollution health outcomes with activation of neuroendocrine sympathetic-adrenal-medullary and hypothalamic–pituitary–adrenal (HPA) stress axes associated with resultant increases in adrenal-derived hormone levels acting as circulating mediators of multi-organ stress reactions. Epidemiological and experimental investigations also demonstrated sex-specific responses to air pollutant inhalation, which may be attributed to hormonal interactions within the stress and reproductive axes. Sex hormones (androgens and estrogens) interact with neuroendocrine functions to influence hypothalamic responses, subsequently augmenting stress-mediated metabolic and immune changes. These neurohormonal interactions may contribute to innate sex-specific responses to inhaled irritants, inducing differing individual susceptibility. The aim of this review was to: (1) examine neuroendocrine co-regulation of the HPA axis by gonadal hormones, (2) provide experimental evidence demonstrating sex-specific respiratory and systemic effects attributed to air pollutant inhalation exposure, and (3) postulate proposed mechanisms of stress and sex hormone interactions during air pollution-related stress. Highlights: Air pollution exposure responses are co-regulated by stress and sex hormones Hypothalamic and CNS stress reactions are sensitive to sex hormones Estrogen and testosterone influence HPA axis induction and glucocorticoid dynamics Neuroendocrine axes interactions mediate sex-specific air pollutant health effects [ABSTRACT FROM AUTHOR]

Gender is one of the most essentialized social categories, with putative differences between cisgender men and cisgender women often framed in biological terms. We propose that the consequences of inaccurate and widely held essentialist beliefs about gonadal hormones (EBAGHs) in particular—that is, that androgens signify "men" and estrogens signify "not-men"—have yet to be fully appreciated. For example, placebo effects such as increased strength, sexual desire, and irritability have been documented for the androgen testosterone. Accumulating research also suggests that lay understandings exaggerate the causal importance of testosterone in men's aggression. Consequently, testosterone is often either eschewed (i.e., men are "poisoned" by it) or enshrined ("more is good, less is bad"). Moreover, the efficacy-bolstering role of estrogens such as estradiol across the physical, cognitive, and sexual health domains for men has been downplayed or ignored by those who assert pejorative links between estrogen and weakness or effeminacy. Critically, EBAGHs may fuel "hypermasculine" behaviors such as excessive red meat consumption, problematic alcohol intake, and anabolic steroid misuse as well as treatment seeking for "low T" in the absence of proper medical diagnosis—which can all, ironically, result in disrupting men's optimal hormonal balance. Implications of our analysis for research (e.g., EBAGHs as predictors men's health behaviors, use of bogus "hormonal profiles" to induce or assuage threats to masculinity in experimental studies) and interventions (e.g., "hormone education" to offset the adverse effects of EBAGHs) are discussed. Public Significance Statement: Inaccurate beliefs about gonadal hormones may cause testosterone to be either valued or devalued—and estrogen to be portrayed as the enemy—in men. Such beliefs may contribute to hypermasculine behaviors, poor diet, misguided health care, and other negative outcomes for men. Biologically accurate hormone education may therefore have beneficial consequences for men's self-perception, perception by others, and overall well-being. [ABSTRACT FROM AUTHOR]

Research into the impacts of oxidative stress (OS), and hormonal balance on reproductive potential has increased over the last 40 years possibly due to rising male infertility. Decreased antioxidant levels and increased OS in tissues result from hormonal imbalance, which in turn leads to male infertility. Increased reactive oxygen species (ROS) generation in seminal plasma has been linked to many lifestyle factors such as alcohol and tobacco use, toxicant exposure, obesity, varicocele, stress, and aging. This article provides an overview of the crosslink between OS and gonadal hormone disruption, as well as a potential mode of action in male infertility. Disrupting the equilibrium between ROS generation and the antioxidant defense mechanism in the male reproductive system may affect key hormonal regulators of male reproductive activities. Unchecked ROS production may cause direct injury on reproductive tissues or could disrupt normal regulatory mechanisms of the hypothalamic-pituitary–gonadal (HPG) axis and its interaction with other endocrine axes, both of which have negative effects on male reproductive health and can lead to male infertility. [ABSTRACT FROM AUTHOR]

Sexual health is an important part of a healthy life. The aim of this study is to define Behçet's sexual dysfunction and the factors affecting it. Sixty-nine patients with Behçet's disease (BD) and 74 healthy controls were included in the study. International Index of Erectile Function (IIEF), the Female Sexual Function Index (FSFI), the Beck Depression Inventory (BDI), and the Short Form Health Survey (SF-36) were filled out by patients and healthy control group (HCG). Follicle-stimulating hormone (FSH), luteinizing hormone (LH), prolactin and estradiol or testosterone levels according to gender were measured in Behçet's patients. The rate of sexual dysfunction and its relationship with gonadal hormones, Beck depression and SF 36 subgroups were evaluated in Behçet's patients. Sixty-nine patients with BD (mean age 39.55 ± 11.7) and 74 HCG (mean age 36.9 ± 6.84) were included in the study. Sexual dysfunction was observed in 74% (49) of BD and 59.5% (44) of HCG (p = 0.047). Prolactin level is within normal limits in all patients. Although there are abnormal levels of gonadal hormones, no relationship was found with sexual dysfunction. Depression especially is more prevalent compared to the healthy population (p = 0.016). The presence of depression negatively affects sexual life. Depression, SF 36 physical role limitations, energy vitality, vitality and mental health were associated with sexual dysfunction in patients with Behçet's disease. Sexual dysfunction was associated with the presence of depression and SF-36 subscales in Behçet's patients. [ABSTRACT FROM AUTHOR]

Anxiety disorders are a major public health concern and current treatments are inadequate for many individuals. Anxiety is more common in women than men and this difference arises during puberty. Sex differences in physiological stress responses may contribute to this variability. During puberty, gonadal hormones shape brain structure and function, but the extent to which these changes affect stress sensitivity is unknown. We examined how pubertal androgens shape behavioral and neural responses to social stress in California mice (Peromyscus californicus), a model species for studying sex differences in stress responses. In adults, social defeat reduces social approach and increases social vigilance in females but not males. We show this sex difference is absent in juveniles, and that prepubertal castration sensitizes adult males to social defeat. Adult gonadectomy does not alter behavioral responses to defeat, indicating that gonadal hormones act during puberty to program behavioral responses to stress in adulthood. Calcium imaging in the medioventral bed nucleus of the stria terminalis (BNST) showed that social threats increased neural activity and that prepubertal castration generalized these responses to less threatening social contexts. These results support recent hypotheses that the BNST responds to immediate threats. Prepubertal treatment with the nonaromatizable androgen dihydrotestosterone acts in males and females to reduce the effects of defeat on social approach and vigilance in adults. These data indicate that activation of androgen receptors during puberty is critical for programming behavioral responses to stress in adulthood.

Opioids are the most prescribed drugs for the alleviation of pain. Both clinical and preclinical studies have reported strong evidence for sex-related divergence regarding opioid analgesia. There is an increasing amount of evidence indicating that gonadal hormones regulate the analgesic efficacy of opioids. This review presents an overview of the importance of gonadal steroids in modulating opioid analgesic responsiveness and focuses on elaborating what is currently known regarding the underlying mechanism. We sought to identify the link between gonadal hormones and the effect of oipiod antinociception. [ABSTRACT FROM AUTHOR]

Abstract Background The aim of this study was to explore the genetic effects of hormones modulated through the pituitary-thyroid/adrenal/gonadal axis on the risk of developing venous thromboembolism (VTE) and to investigate the potentially causal relationships between them. Methods A two-sample Mendelian randomization (MR) design was used. The single-nucleotide polymorphisms (SNPs) used as instrumental variables for various hormones and hormone-mediated diseases were derived from published genome-wide association studies (GWASs). Summary statistics for the risk of developing VTE (including deep venous thrombosis [DVT] and pulmonary embolism [PE]) were obtained from the UK Biobank and the FinnGen consortium. Inverse-variance weighting (IVW) was applied as the primary method to analyse causal associations. Other MR methods were used for supplementary estimates and sensitivity analysis. Results A genetic predisposition to greater free thyroxine (FT4) concentrations was associated with a greater risk of developing DVT (OR = 1.0007, 95%CI [1.0001–1.0013], p = 0.0174) and VTE (OR = 1.0008, 95%CI [1.0002–1.0013], p = 0.0123). Genetically predicted hyperthyroidism was significantly associated with an increased risk of developing DVT (OR = 1.0685, 95%CI [1.0139–1.1261], p = 0.0134) and VTE (OR = 1.0740, 95%CI [1.0165–1.1348], p = 0.0110). According to the initial MR analysis, testosterone concentrations were positively associated with the risk of developing VTE (OR = 1.0038, 95%CI [1.004–1.0072], p = 0.0285). After sex stratification, estradiol concentrations were positively associated with the risk of developing DVT (OR = 1.0143, 95%CI [1.0020–1.0267], p = 0.0226) and VTE (OR = 1.0156, 95%CI [1.0029–1.0285], p = 0.0158) in females, while the significant relationship between testosterone and VTE did not persist. SHBG rs858518 was identified as the only SNP that was associated with an increased risk of developing VTE, mediated by estradiol, in females. Conclusions Genetically predicted hyperthyroidism and increased FT4 concentrations were positively associated with the risk of developing VTE. The effects of genetically predicted sex hormones on the risk of developing VTE differed between males and females. Greater genetically predicted estradiol concentrations were associated with an increased risk of developing VTE in females, while the SHBG rs858518 variant may become a potential prevention and treatment target for female VTE.

Menopause is a biological process experienced by all people assigned female at birth. A significant number of women experience mental ill health related to the major brain gonadal hormone shifts that occur in their midlife. There is poor understanding and management of the complex mental ill health issues, with the biological brain hormone changes receiving little formal attention. The current treatment advice is to manage this special type of mental ill health in the same way that all mental ill health is managed. This leads to poor outcomes for women and their families. Many women leave the workforce earlier than expected due to menopause-related depression and anxiety, with subsequent loss of salary and superannuation. Others describe being unable to adequately parent or maintain meaningful relationships – all ending in a poor quality of life. We are a large and diverse group of national and international clinicians, lived experience and social community advocates, all working together to innovate the current approaches available for women with menopausal mental ill health. Above all, true innovation is only possible when the woman with lived experience of menopause is front and centre of this debate. [ABSTRACT FROM AUTHOR]

Background: The aim of this study was to explore the genetic effects of hormones modulated through the pituitary-thyroid/adrenal/gonadal axis on the risk of developing venous thromboembolism (VTE) and to investigate the potentially causal relationships between them. Methods: A two-sample Mendelian randomization (MR) design was used. The single-nucleotide polymorphisms (SNPs) used as instrumental variables for various hormones and hormone-mediated diseases were derived from published genome-wide association studies (GWASs). Summary statistics for the risk of developing VTE (including deep venous thrombosis [DVT] and pulmonary embolism [PE]) were obtained from the UK Biobank and the FinnGen consortium. Inverse-variance weighting (IVW) was applied as the primary method to analyse causal associations. Other MR methods were used for supplementary estimates and sensitivity analysis. Results: A genetic predisposition to greater free thyroxine (FT4) concentrations was associated with a greater risk of developing DVT (OR = 1.0007, 95%CI [1.0001–1.0013], p = 0.0174) and VTE (OR = 1.0008, 95%CI [1.0002–1.0013], p = 0.0123). Genetically predicted hyperthyroidism was significantly associated with an increased risk of developing DVT (OR = 1.0685, 95%CI [1.0139–1.1261], p = 0.0134) and VTE (OR = 1.0740, 95%CI [1.0165–1.1348], p = 0.0110). According to the initial MR analysis, testosterone concentrations were positively associated with the risk of developing VTE (OR = 1.0038, 95%CI [1.004–1.0072], p = 0.0285). After sex stratification, estradiol concentrations were positively associated with the risk of developing DVT (OR = 1.0143, 95%CI [1.0020–1.0267], p = 0.0226) and VTE (OR = 1.0156, 95%CI [1.0029–1.0285], p = 0.0158) in females, while the significant relationship between testosterone and VTE did not persist. SHBG rs858518 was identified as the only SNP that was associated with an increased risk of developing VTE, mediated by estradiol, in females. Conclusions: Genetically predicted hyperthyroidism and increased FT4 concentrations were positively associated with the risk of developing VTE. The effects of genetically predicted sex hormones on the risk of developing VTE differed between males and females. Greater genetically predicted estradiol concentrations were associated with an increased risk of developing VTE in females, while the SHBG rs858518 variant may become a potential prevention and treatment target for female VTE. [ABSTRACT FROM AUTHOR]

In our study, the protective role of synthetic aromatase inhibitors anastrozole (ANS), letrozole (LTZ) and exemestane (EXM) and natural aromatase inhibitors resveratrol (RSV) and apigenin (APG) against testicular failure caused by exposure to Bisphenol A (BPA) was investigated. The epididymal sperm concentration, sperm motility and sperm morphology were determined. Oxidative stress and inflammatory response parameters were examined and histological examinations were performed in testicular tissues. Our results revealed that BPA exposure decreased serum testosterone and estrogen levels, increased FSH and LH levels (p < 0.05). BPA has been found to increase oxidative stress and inflammatory response and disrupt the histological structure. Also, BPA exposure decreased testicular weight, epididymal sperm concentration and motility, and increased abnormal sperm rate (p < 0.05). These results show that ANS, LTZ and RSV treatments reduce the BPA-induced testicular damage. [ABSTRACT FROM AUTHOR]

Evidence abounds that gut microbiome components are associated with sex disparities in the immune system. However, it remains unclear whether the observed sex disparity in asthma incidence is associated with sex-dependent differences in immune-modulating gut microbiota, and/or its influence on allergic airway inflammatory processes. Using a mouse model of house dust mite (HDM)-induced allergic inflammation and the four core genotypes (FCGs) model, we have previously reported sex differences in lung inflammatory phenotypes. Here, we investigated associations of gut microbiomes with these phenotypes by challenging FCG mice [mouse with female sex chromosome and male gonad (XXM), mouse with female sex chromosome and female gonad (XXF), mouse with male sex chromosome and male gonad (XYM), and mouse with male sex chromosome and female gonad (XYF); n = 7/group] with HDM (25 μg) or PBS intranasally for 5 wk and collecting fecal samples. We extracted fecal DNA and analyzed the 16S microbiome via Targeted Metagenomic Sequencing. We compared α and β diversity across genotypes and assessed the Firmicutes/Bacteroidetes (F/B) ratio. When comparing baseline and after exposure for the FCG, we found that the gut F/B ratio was only increased in the XXM genotype. We also found that α diversity was significantly increased in all FCG mice upon HDM challenge, with the highest increase in the XXF, and the lowest in the XXM genotypes. Similarly, β diversity of the microbial community was also affected by challenge in a gonad- and chromosome-dependent manner. In summary, our results indicated that HDM treatment, gonads, and sex chromosomes significantly influence the gut microbial community composition. We concluded that allergic lung inflammation may be affected by the gut microbiome in a sex-dependent manner involving both hormonal and genetic influences. NEW & NOTEWORTHY: Recently, the gut microbiome and its role in chronic respiratory disease have been the subject of extensive research and the establishment of its involvement in immune functions. Using the FCG mouse model, our findings revealed the influence of gonads and sex chromosomes on the microbial community structure before and after exposure to HDM. Our data provide a potential new avenue to better understand mediators of sex disparities associated with allergic airway inflammation. [ABSTRACT FROM AUTHOR]

Abstract Background Human immunodeficiency virus/acquired immunodeficiency syndrome (HIV/AIDS) is an endemic chronic disease which is characterized with progressive depletion of CD4 T cells and increased susceptibility to opportunistic infections. Previous studies have associated HIV infection with increased hypogonadism. However, the prevalence of hypogonadism remained poorly defined and widely ranging in various studies. This study aims to evaluate the serum gonadal hormonal levels and hypogonadism in antiretroviral therapy (ART) naïve newly diagnosed HIV infected-males in Mwanza, Tanzania. Methods This was a comparison study involving 81 ART naïve newly diagnosed HIV-infected adult males as study group and 81 apparently healthy HIV-negative males as comparison group. The participants in the study group and comparison group were matched by body mass index and age. Serum hormones [Total testosterone (TT), follicle stimulating hormone (FSH), luteinizing hormone (LH) and estradiol (E) were estimated. Serum testosterone 300 ng/dl with high LH and FSH (compensatory hypogonadism) were taken as markers of hypogonadism. Data were analyzed using STATA version 15. Results The median serum testosterone level among ART naïve newly diagnosed HIV-infected adult males was significantly lower as compared to their comparison group (447 [259–534] versus 517 [396–605]; p = 0.0074) and shown to decrease with decreasing CD4 level. The median [IQR] serum FSH level among ART naïve newly diagnosed HIV-infected adult males was significantly higher than among their comparison group (3.8 [2.1–6.5] versus 2.6 [1.8–4.2]; p = 0.0086). The differences in serum LH and Estradiol were not statistically significant. Furthermore, the proportion of hypogonadism was significantly higher among ART naïve newly diagnosed HIV-infected adult males than in their comparison group (37.0% [30/81] versus 14.8% [12/81]; p = 0.0006). Out of these 30, 24 HIV-infected males had secondary hypogonadism, one had primary, and the remaining five had compensatory hypogonadism. Conclusion Serum testosterone was lower and follicle stimulating hormone was higher among ART naïve HIV-infected males as compared to the HIV negative controls. Hypogonadism, mainly secondary, is common endocrine abnormality among ART naïve HIV-infected male patients in this study. HIV is associated with variations in gonadal hormones which may lead to sexual dysfunction in infected individuals.

Background: Human immunodeficiency virus/acquired immunodeficiency syndrome (HIV/AIDS) is an endemic chronic disease which is characterized with progressive depletion of CD4 T cells and increased susceptibility to opportunistic infections. Previous studies have associated HIV infection with increased hypogonadism. However, the prevalence of hypogonadism remained poorly defined and widely ranging in various studies. This study aims to evaluate the serum gonadal hormonal levels and hypogonadism in antiretroviral therapy (ART) naïve newly diagnosed HIV infected-males in Mwanza, Tanzania. Methods: This was a comparison study involving 81 ART naïve newly diagnosed HIV-infected adult males as study group and 81 apparently healthy HIV-negative males as comparison group. The participants in the study group and comparison group were matched by body mass index and age. Serum hormones [Total testosterone (TT), follicle stimulating hormone (FSH), luteinizing hormone (LH) and estradiol (E) were estimated. Serum testosterone < 300 ng/dl, or testosterone > 300 ng/dl with high LH and FSH (compensatory hypogonadism) were taken as markers of hypogonadism. Data were analyzed using STATA version 15. Results: The median serum testosterone level among ART naïve newly diagnosed HIV-infected adult males was significantly lower as compared to their comparison group (447 [259–534] versus 517 [396–605]; p = 0.0074) and shown to decrease with decreasing CD4 level. The median [IQR] serum FSH level among ART naïve newly diagnosed HIV-infected adult males was significantly higher than among their comparison group (3.8 [2.1–6.5] versus 2.6 [1.8–4.2]; p = 0.0086). The differences in serum LH and Estradiol were not statistically significant. Furthermore, the proportion of hypogonadism was significantly higher among ART naïve newly diagnosed HIV-infected adult males than in their comparison group (37.0% [30/81] versus 14.8% [12/81]; p = 0.0006). Out of these 30, 24 HIV-infected males had secondary hypogonadism, one had primary, and the remaining five had compensatory hypogonadism. Conclusion: Serum testosterone was lower and follicle stimulating hormone was higher among ART naïve HIV-infected males as compared to the HIV negative controls. Hypogonadism, mainly secondary, is common endocrine abnormality among ART naïve HIV-infected male patients in this study. HIV is associated with variations in gonadal hormones which may lead to sexual dysfunction in infected individuals. [ABSTRACT FROM AUTHOR]

Understanding sex differences in physiology and disease requires the identification of the molecular agents that cause phenotypic sex differences. Two groups of such agents are genes located on the sex chromosomes, and gonadal hormones. The former have coherent linkage to chromosomes that form differently in the two sexes under the influence of genomic forces that are not related to reproductive function, whereas the latter have a direct or indirect relationship to reproduction. Evidence published in the past 5 years supports the identification of several agents of sexual differentiation encoded by the X chromosome in mice, including Kdm5c, Kdm6a, Ogt and Xist. These X chromosome agents have wide pleiotropic effects, potentially influencing sex differences in many different tissues, a characteristic shared with the gonadal hormones. The identification of X chromosome agents of sexual differentiation will facilitate understanding of complex intersecting gene pathways underlying sex differences in disease.

Abstract Proper cerebrovascular development and neurogliovascular unit assembly are essential for brain growth and function throughout life, ensuring the continuous supply of nutrients and oxygen. This involves crucial events during pre- and postnatal stages through key pathways, including vascular endothelial growth factor (VEGF) and Wnt signaling. These pathways are pivotal for brain vascular growth, expansion, and blood–brain barrier (BBB) maturation. Interestingly, during fetal and neonatal life, cerebrovascular formation coincides with the early peak activity of the hypothalamic-pituitary-gonadal axis, supporting the idea of sex hormonal influence on cerebrovascular development and barriergenesis. Sex hormonal dysregulation in early development has been implicated in neurodevelopmental disorders with highly sexually dimorphic features, such as autism spectrum disorder (ASD) and attention-deficit/hyperactivity disorder (ADHD). Both disorders show higher prevalence in men, with varying symptoms between sexes, with boys exhibiting more externalizing behaviors, such as aggressivity or hyperactivity, and girls displaying higher internalizing behaviors, including anxiety, depression, or attention disorders. Indeed, ASD and ADHD are linked to high prenatal testosterone exposure and reduced aromatase expression, potentially explaining sex differences in prevalence and symptomatology. In line with this, high estrogen levels seem to attenuate ADHD symptoms. At the cerebrovascular level, sex- and region-specific variations of cerebral blood flow perfusion have been reported in both conditions, indicating an impact of gonadal hormones on the brain vascular system, disrupting its ability to respond to neuronal demands. This review aims to provide an overview of the existing knowledge concerning the impact of sex hormones on cerebrovascular formation and maturation, as well as the onset of neurodevelopmental disorders. Here, we explore the concept of gonadal hormone interactions with brain vascular and BBB development to function, with a particular focus on the modulation of VEGF and Wnt signaling. We outline how these pathways may be involved in the underpinnings of ASD and ADHD. Outstanding questions and potential avenues for future research are highlighted, as uncovering sex-specific physiological and pathological aspects of brain vascular development might lead to innovative therapeutic approaches in the context of ASD, ADHD and beyond.

Proper cerebrovascular development and neurogliovascular unit assembly are essential for brain growth and function throughout life, ensuring the continuous supply of nutrients and oxygen. This involves crucial events during pre- and postnatal stages through key pathways, including vascular endothelial growth factor (VEGF) and Wnt signaling. These pathways are pivotal for brain vascular growth, expansion, and blood–brain barrier (BBB) maturation. Interestingly, during fetal and neonatal life, cerebrovascular formation coincides with the early peak activity of the hypothalamic-pituitary-gonadal axis, supporting the idea of sex hormonal influence on cerebrovascular development and barriergenesis. Sex hormonal dysregulation in early development has been implicated in neurodevelopmental disorders with highly sexually dimorphic features, such as autism spectrum disorder (ASD) and attention-deficit/hyperactivity disorder (ADHD). Both disorders show higher prevalence in men, with varying symptoms between sexes, with boys exhibiting more externalizing behaviors, such as aggressivity or hyperactivity, and girls displaying higher internalizing behaviors, including anxiety, depression, or attention disorders. Indeed, ASD and ADHD are linked to high prenatal testosterone exposure and reduced aromatase expression, potentially explaining sex differences in prevalence and symptomatology. In line with this, high estrogen levels seem to attenuate ADHD symptoms. At the cerebrovascular level, sex- and region-specific variations of cerebral blood flow perfusion have been reported in both conditions, indicating an impact of gonadal hormones on the brain vascular system, disrupting its ability to respond to neuronal demands. This review aims to provide an overview of the existing knowledge concerning the impact of sex hormones on cerebrovascular formation and maturation, as well as the onset of neurodevelopmental disorders. Here, we explore the concept of gonadal hormone interactions with brain vascular and BBB development to function, with a particular focus on the modulation of VEGF and Wnt signaling. We outline how these pathways may be involved in the underpinnings of ASD and ADHD. Outstanding questions and potential avenues for future research are highlighted, as uncovering sex-specific physiological and pathological aspects of brain vascular development might lead to innovative therapeutic approaches in the context of ASD, ADHD and beyond. [ABSTRACT FROM AUTHOR]

Sex differences in the brain are reflected at the molecular, structural, and behavioral levels, and are observed across brain disorders. Brain sexual differentiation is a dynamic process throughout life, resulting from interactions of gonadal hormones, sex chromosomes, and the environment. Studies of sex-specific factors, such as perinatal testosterone exposure in males and the estrous cycle in females, show clear evidence that epigenetic mechanisms drive sex differences in the brain and behavior. Studies of environmental impact on the brain epigenome across the lifespan have also revealed important sex differences but with more limited mechanistic insights. Future neuroepigenetic studies incorporating sex-related variables and better-targeted, higher-resolution approaches are hoped to maximize the benefit of insights gained from basic research for people across genders. Sex differences are found across brain regions, behaviors, and brain diseases. Sexual differentiation of the brain is initiated prenatally but it continues throughout life, as a result of the interaction of three major factors: gonadal hormones, sex chromosomes, and the environment. These factors are thought to act, in part, via epigenetic mechanisms which control chromatin and transcriptional states in brain cells. In this review, we discuss evidence that epigenetic mechanisms underlie sex-specific neurobehavioral changes during critical organizational periods, across the estrous cycle, and in response to diverse environments throughout life. We further identify future directions for the field that will provide novel mechanistic insights into brain sex differences, inform brain disease treatments and women's brain health in particular, and apply to people across genders. [ABSTRACT FROM AUTHOR]

The cystic fibrosis transmembrane conductance regulator (CFTR) is a cAMP-activated trans-membrane ATP gated anion channel present in most epithelia, which transports chloride and bicarbonate ions across the apical membrane. Mutations in the CFTR protein are known to result in defective expression or function, notably the inhibition of chloride and bicarbonate transport. This can result in cystic fibrosis (CF), a disorder characterised by thickness of the mucus lining of the epithelial cells of the alimentary and respiratory tracts, sweat ducts and reproductive organs. As a consequence, there is a reduction in fluid transport at the apical surface. While the most devastating effect of CF is mortality, about 98% of men with CF are infertile, consequent of early blockage of or failure to develop the mesonephrotic ducts as well as the vas deferens. The effect of CF of female fertility is less well-understood. This review highlights the genetics and pathophysiology as well as the mechanism of action of CF on female infertility. [ABSTRACT FROM AUTHOR]

To compare menstrual health literacy among adolescents and young adults on the basis of family religious background and United States region We conducted a cross-sectional online survey of post-menarcheal US adolescents and young adults aged 14-24 years who identified their family religious background, including Christian or non-religious, with recruitment via the social media platform TikTok. We asked participants several questions to assess their health literacy regarding common myths about the use of gonadal steroid hormones for menstrual suppression. From 3250 online survey respondents, 2997 met the criteria for analysis, with 1989 identifying their family as Christian (66.4%) and 1008 identifying their family as non-religious (33.6%), with equal representation by US region. Health literacy was lower among those with a Christian family background, with concerns that menstrual suppression is unhealthy (16.4% vs 10.5% with non-religious background, P <.01), is unsafe (31.4% vs 24.2%, P <.01), and could lead to infertility (32.6% vs 20.0%, P <.01). Similarly, adolescents and young adults from the US South were worried that menstrual suppression is unhealthy (31.5%; P <.01) and would lead to infertility (33.8%; P <.01). Health literacy is lower among adolescents and young adults with a Christian family background and those who live in the South. These results demonstrate a need for an evidence-based national curriculum that addresses the safe and effective use of hormonal medications for menstrual suppression. [ABSTRACT FROM AUTHOR]

Sex differences in physiology and disease in mammals result from the effects of three classes of factors that are inherently unequal in males and females: reversible (activational) effects of gonadal hormones, permanent (organizational) effects of gonadal hormones, and cell-autonomous effects of sex chromosomes, as well as genes driven by these classes of factors. Often, these factors act together to cause sex differences in specific phenotypes, but the relative contribution of each and the interactions among them remain unclear. Here, we used the four core genotypes (FCG) mouse model with or without hormone replacement to distinguish the effects of each class of sex-biasing factors on transcriptome regulation in liver and adipose tissues. We found that the activational hormone levels have the strongest influence on gene expression, followed by the organizational gonadal sex effect, and last, sex chromosomal effect, along with interactions among the three factors. Tissue specificity was prominent, with a major impact of estradiol on adipose tissue gene regulation and of testosterone on the liver transcriptome. The networks affected by the three sex-biasing factors include development, immunity and metabolism, and tissue-specific regulators were identified for these networks. Furthermore, the genes affected by individual sex-biasing factors and interactions among factors are associated with human disease traits such as coronary artery disease, diabetes, and inflammatory bowel disease. Our study offers a tissue-specific account of the individual and interactive contributions of major sex-biasing factors to gene regulation that have broad impact on systemic metabolic, endocrine, and immune functions.

Autism spectrum disorder (ASD) is a neurodevelopmental condition with a prevalence rate of 2.78%, and it is characterized by deficits in sociability and communication and restricted patterns of interests and activities. Remarkably, this psychiatric disorder exhibits a pronounced gender bias, with 80% of children diagnosed with ASD being boys. In this review, we will present advancements in mouse models of ASD and their potential contributions to our understanding of the disorder. We will highlight how initial pre-clinical investigations focused solely on male mice due to the gender bias in ASD and explain why we believe that this approach might have had detrimental consequences regarding our understanding of ASD etiology and pathophysiology. We will highlight the evidence of two sensitive periods during brain development when differential exposure to gonadal hormones may result in sex differences in brain function and behavior: the perinatal period and the pre-pubertal period. Finally, we will suggest neuroinflammation as a feasible biological mechanism that may converge different ASD etiological factors and cellular mechanisms into a brain sexual differentiation context, thus accounting for the gender disparities observed in the disorder.

Autism spectrum disorder (ASD) is a neurodevelopmental condition with a prevalence rate of 2.78%, and it is characterized by deficits in sociability and communication and restricted patterns of interests and activities. Remarkably, this psychiatric disorder exhibits a pronounced gender bias, with 80% of children diagnosed with ASD being boys. In this review, we will present advancements in mouse models of ASD and their potential contributions to our understanding of the disorder. We will highlight how initial pre-clinical investigations focused solely on male mice due to the gender bias in ASD and explain why we believe that this approach might have had detrimental consequences regarding our understanding of ASD etiology and pathophysiology. We will highlight the evidence of two sensitive periods during brain development when differential exposure to gonadal hormones may result in sex differences in brain function and behavior: the perinatal period and the pre-pubertal period. Finally, we will suggest neuroinflammation as a feasible biological mechanism that may converge different ASD etiological factors and cellular mechanisms into a brain sexual differentiation context, thus accounting for the gender disparities observed in the disorder. [ABSTRACT FROM AUTHOR]

Purpose: Benign prostatic hyperplasia (BPH) is the main prevalent disorder in men over forty years, usually revealing itself with lower urinary tract symptoms. Despite the existence of different treatments, the incidence of BPH is increasing, so further studies for better management are a necessity. This research was designed to assay the effectiveness of nano-micellar curcumin on biomedical indicators of patients with BPH. Methods: The present research was a double-blind, randomized, and placebo-controlled trial that enrolled fifty-two patients with BPH between June 2021 and December 2021. Participants were randomized to receive 160 mg/d nano-micellar curcumin (n = 26) or placebo (n = 26) as soft gel during 3 months. Primary end point was changes in International Prostate Symptoms Score (IPSS). Data gathering was occurred using a standard inquiry form and measuring other biomedical parameters based on routine laboratory techniques. To compare the distribution of demographics and covariates, independent t-test and Chi-square were used. Results: Nano-micellar curcumin had significant effect on IPSS (p value: 0.010), low effect on high-sensitive C-reactive protein (hs-CRP) (p value: 0.032), and low to intermediate effect on malondialdehyde (MDA) (p value: 0.014) level as secondary end points after the intervention. The effect of nano-micellar curcumin on other parameters was negligible. Conclusion: Overall, this trial indicated 3-month intake of nano-micellar curcumin had considerable effects on IPSS as the most common clinical symptom and also two biomedical parameters including serum hs-CRP and MDA. Trial registration: http://www.irct.ir: IRCT20170430033730N3. [ABSTRACT FROM AUTHOR]

Abstract Background and aims Cortical spreading depression (CSD), a transient neuronal and glial depolarization that propagates slowly across the cerebral cortex, is the putative electrophysiological event underlying migraine aura and a headache trigger. Migraine is three times more prevalent in women than men, linked to circulating female hormones. High estrogen levels or estrogen withdrawal may be a migraine trigger for many women. We, therefore, aimed to examine whether sex, gonadectomy, and female hormone supplementation and withdrawal affect the susceptibility to CSD. Methods To determine CSD susceptibility, we recorded the frequency of CSDs triggered during 2-h topical KCl application in intact or gonadectomized female and male rats, without or with estradiol or progesterone supplementation via daily intraperitoneal injections. Estrogen or progesterone treatment followed by withdrawal was studied in a separate cohort. To take the first step towards identifying potential mechanisms, we studied glutamate and GABAA receptor binding using autoradiography. Results The CSD frequency in intact female rats was higher than intact male and ovariectomized rats. We did not detect a change in CSD frequency during different stages of the estrous cycle in intact females. Daily estrogen injections for three weeks did not change CSD frequency. However, one-week estrogen withdrawal after two weeks of treatment significantly increased CSD frequency compared with the vehicle group in gonadectomized females. The same protocol of estrogen treatment and withdrawal was ineffective in gonadectomized males. In contrast to estrogen, daily progesterone injections for three weeks elevated CSD susceptibility, and one-week withdrawal after two weeks of treatment partially normalized this effect. Autoradiography did not reveal significant changes in glutamate or GABAA receptor binding density after estrogen treatment and withdrawal. Conclusions These data suggest that females are more susceptible to CSD, and sexual dimorphism is abrogated by gonadectomy. Moreover, estrogen withdrawal after prolonged daily treatment enhances CSD susceptibility. These findings may have implications for estrogen-withdrawal migraine, although the latter tends to be without aura.

The article discusses the potential benefits of menopausal hormone therapy for women with schizophrenia. It highlights the increased risk of relapse in women with schizophrenia during the menopause transition and suggests that hormone therapy may help reduce this risk. The article presents findings from a nationwide cohort study that showed a 16% decreased risk of psychosis relapse in women who used menopausal hormone therapy. However, the article also acknowledges that further research is needed to fully establish the effectiveness and safety of hormone therapy as an adjunctive treatment for schizophrenia. [Extracted from the article]

Extensive practice and knowledge of the methods and effects of castration of male livestock and even humans has been widespread since ancient times, but only a few decades ago did neutering (including spaying) become a routine part of canine husbandry. In the US, the 6-month neuter became standard practice. Only recently, however, have some of the consequences of this major physiological alteration become evident. As the data-based study on 35 breeds reveals, there are major breed differences associated with effects of neutering, especially with early neutering, including increased risks of joint disorders and some cancers. The study of mixed-breed dogs reveals that the risk of joint disorders is increased in the large dogs. Implications of breed-specific and sex-specific effects for age of neutering have prompted the consideration of a new paradigm with regard to this practice. This involves focusing on each individual dog when deciding upon the appropriate age of neutering to avoid increasing the risk of a joint disorder or cancer above that inherent for the breed. For many breeds, particularly the smaller dogs, no effects were found for the age of neutering on joint disorders and the cancers followed. In these cases, the caregiver has a wide range of choice for neutering without increasing the dog's risk for these diseases. In the future, additional research may reveal more about other increased risks for age-related cognitive dysfunction or elevated levels of luteinizing hormone caused by gonad removal, and lead to revised guidelines.

Introduction: The combined oral contraceptive (COC) pill is often employed to address physical and neurological symptoms in menstrual cycle-related disorders by suppressing shifts in endogenous gonadal hormone fluctuations. Symptom persistence, especially in the lead up to the hormone-free interval (HFI), suggests an underlying neurobiological mechanism of preserved cycling. Our study utilised a non-invasive method of visually inducing long-term potentiation (LTP) to index changes in neural plasticity in the absence of hormonal fluctuations. Methods: Visually induced LTP was recorded using electroencephalography in 24 healthy female COC users across three sessions: days 3 and 21 during active hormone pills, and day 24 during the HFI. The Daily Record of the Severity of Problems (DRSP) questionnaire tracked premenstrual symptoms. Dynamic causal modelling (DCM) was used to elucidate the neural connectivity and receptor activity changes associated with LTP across different days of COC. Results: Visually induced LTP was greater on day 21 than day 3 (p = 0.011) and was localised to the P2 visually evoked potential. There was no effect of the HFI (day 24) on LTP. DCM of differences between days 3 and 21 showed changes to inhibitory interneuronal gating of LTP in cortical layer VI. The DRSP only showed a significant increase in symptoms in the HFI, meaning the LTP result appeared more sensitive to cyclicity. Conclusions: This study provides objective evidence of preserved cyclicity in COC users through enhanced LTP on day 21 compared to day 3 of a 28-day COC regimen, indicating that relatively higher excitation in the brain despite peripheral gonadal suppression may underlie and exacerbate menstrual cycle-related disorders. [ABSTRACT FROM AUTHOR]

Introduction: Environmental pollutants could be implicated in female endocrine setting Q6 beyond traditional factors. Until now, few study has focused on the association of environmental exposure to heavy metals with sex hormones in postmenopausal women. This study intended to investigate whether serum levels of heavy metals(i.e., Cd, Pb, Hg, Mn, Se) would influence sex hormones in postmenopausal women. Methods and results: A cross-sectional study was performed on 614 nationally representative participants from 2013-2016 National Health and Nutrition Examination Survey (NHANES) in the US. Multivariate linear regression models and restricted cubic spline plots revealed cadmium(Cd) had linear positive association with TT(b=3.25, 95%CI= 1.12, 5.38), bioavailable TT(b=1.78, 95% CI=0.36,3.21) and TT/E2(b=0.76, 95%CI=0.28,1.24), which was more apparent in natural menopausal and obese women. Lead(Pb) had linear positive association with SHBG(b=12.84, 95%CI= 6.77,18.91), which was apparent in nearly all subgroups except in normal BMI group, and TT/E2 (b=0.69, 95%CI 0.134,1.25), which was apparent in natural menopausal and normal BMI women. Manganese(Mn) had non-linear association with SHBG, which was more apparent in natural menopausal and obese women, and TT/E2, which was more apparent in natural menopausal and normal BMI women. Selenium(Se) had U shaped non-linear association with TT, which was more apparent in hysterectomy, overweight and obese women, and SHBG, which was apparent in nearly all subgroups except in normal BMI group. Conclusion: In summary, this cross-sectional study indicates a possible role that various degree of environmental exposure to heavy metals plays in the disruption of sex Q5 hormone levels in postmenopausal women. Further experiments are needed to elucidate the underlying mechanisms. [ABSTRACT FROM AUTHOR]

Circadian clocks can be traced in nearly all life kingdoms, with the male reproductive system no exception. However, our understanding of the circadian clock in spermatogenesis seems to fall behind other scenarios. The present review aims to summarize the current knowledge about the role and especially the potential mechanisms of clock genes in spermatogenesis regulation. Accumulating studies have revealed rhythmic oscillation in semen parameters and some physiological events of spermatogenesis. Disturbing the clock gene expression by genetic mutations or environmental changes will also notably damage spermatogenesis. On the other hand, the mechanisms of spermatogenetic regulation by clock genes remain largely unclear. Some recent studies, although not revealing the entire mechanisms, indeed attempted to shed light on this issue. Emerging clues hinted that gonadal hormones, retinoic acid signaling, homologous recombination, and the chromatoid body might be involved in the regulation of spermatogenesis by clock genes. Then we highlight the challenges and the promising directions for future studies so as to stimulate attention to this critical field which has not gained adequate concern. [ABSTRACT FROM AUTHOR]

Clinical scientists have been investigating the relationships between sex hormones, personality, and eating disorders for decades. However, there is a lack of direct research that addresses whether personality mediates or moderates the relationships between sex hormones and eating pathology. Moreover, the neural mechanisms that underlie the interactive associations between these variables remain unclear. This review aims to summarize the associations between these constructs, describe a neural mechanism mediating these relationships, and offer clinical strategies for the early identification and intervention of eating disorders. The gathered evidence shows that aggressiveness, impulsivity, and obsessive-compulsiveness may mediate or moderate the relationships between sex hormones and eating pathology, but only among females. Furthermore, sex hormone receptor density in the mesocorticolimbic dopamine pathway may explain the neural mechanism of these associations. Future research should use more comprehensive personality measurements and assess the mediation and moderation effects of temperament while taking the hormone levels of women across menstrual cycles into account. Additionally, electroencephalography and functional magnetic resonance imaging should be implemented to directly assess brain activity and corroborate these findings. [ABSTRACT FROM AUTHOR]

Visceral pain and stress are tightly intertwined bodily and emotional phenomena, which enable a flexible adaptation to environmental challenges by activating a response repertoire to restore homeostasis along the gut-brain axis. However, visceral pain and stress can persist widely independent of the initial cause, acquiring independent disease values and posing major health burdens as predominant features in disorders of gut-brain interaction (DGBI). Epidemiological data consistently documents an increased prevalence for women to suffer from chronic visceral pain, possibly shaped by sex hormones and modulated by stress and its biological and psychosocial correlates. Yet, mechanisms underlying the complex interactions between altered visceroception, stress and sex remain widely elusive, especially in clinical populations with DGBI. We herein selectively review mechanisms of interactions between stress and sex in the complex pathophysiology of DGBI. A particular emphasis is laid on visceral pain, in which stress constitutes a major risk factor as well as mediator, and sex-related differences are particularly pronounced. Building on the neurobiology of stress and mechanisms of gut-brain interactions, we highlight putative target mechanisms via which visceral pain and stress may converge with sex effects into a triad. Accommodating a global demographic shift, we propose a lifespan perspective in future research, which may enable a more fine-tuned evaluation of this complex interplay exerting distinct challenges during vulnerable developmental phases. This viewpoint may advance our understanding of pathophysiological processes and can ultimately inspire novel tailored prevention strategies and therapeutic approaches in the treatment of chronic visceral pain and DGBI across the lifespan. [ABSTRACT FROM AUTHOR]

Polycystic ovary syndrome (PCOS) is a common gynecological endocrine disorder. Pomegranate juice (PJ) has been known to play anti‐inflammatory and antioxidant roles. However, the effects of PJ on inflammation, oxidative stress, and sex hormones in PCOS patients are very little studied, and thus more studies are needed. This randomized controlled trial enrolled 44 women diagnosed with PCOS according to the Rotterdam criteria, body mass index (BMI) ≥ 25 kg/m2, and aged 18–40 years old. Participants were randomly assigned to take 45 ml/day of concentrated PJ or a control group without intervention. Some biomarkers of sex hormones, inflammation, and oxidative stress were quantified at baseline and after the 8‐week intervention. Compared with the controls, serum testosterone levels were significantly decreased in overweight and obese women with PCOS who supplemented with concentrated PJ (−0.004 ± 0.013 vs. 0.039 ± 0.013, p =.039). However, we did not observe significant differences in luteinizing hormone (LH) and sex hormone‐binding globulin (SHBG) levels and inflammation and oxidative stress factors between the two groups after adjustment for confounding variables. An 8‐week supplementation with concentrated PJ could effectively improve testosterone levels in overweight and obese women with PCOS. This study was registered at www.irct.ir (IRCT20191109045383N1). [ABSTRACT FROM AUTHOR]

Adolescence is characterized by rapid brain development in white matter (WM) that is attributed in part to surges in gonadal hormones. To date, however, there have been few longitudinal investigations relating changes in gonadal hormones and WM development in adolescents. We acquired diffusion-weighted MRI to estimate mean fractional anisotropy (FA) from 10 WM tracts and salivary testosterone from 51 females and 29 males (ages 9-14 years) who were matched on pubertal stage and followed, on average, for 2 years. We tested whether interactions between sex and changes in testosterone levels significantly explained changes in FA. We found positive associations between changes in testosterone and changes in FA within the corpus callosum, cingulum cingulate, and corticospinal tract in females (all ps

Background and aims: Cortical spreading depression (CSD), a transient neuronal and glial depolarization that propagates slowly across the cerebral cortex, is the putative electrophysiological event underlying migraine aura and a headache trigger. Migraine is three times more prevalent in women than men, linked to circulating female hormones. High estrogen levels or estrogen withdrawal may be a migraine trigger for many women. We, therefore, aimed to examine whether sex, gonadectomy, and female hormone supplementation and withdrawal affect the susceptibility to CSD. Methods: To determine CSD susceptibility, we recorded the frequency of CSDs triggered during 2-h topical KCl application in intact or gonadectomized female and male rats, without or with estradiol or progesterone supplementation via daily intraperitoneal injections. Estrogen or progesterone treatment followed by withdrawal was studied in a separate cohort. To take the first step towards identifying potential mechanisms, we studied glutamate and GABAA receptor binding using autoradiography. Results: The CSD frequency in intact female rats was higher than intact male and ovariectomized rats. We did not detect a change in CSD frequency during different stages of the estrous cycle in intact females. Daily estrogen injections for three weeks did not change CSD frequency. However, one-week estrogen withdrawal after two weeks of treatment significantly increased CSD frequency compared with the vehicle group in gonadectomized females. The same protocol of estrogen treatment and withdrawal was ineffective in gonadectomized males. In contrast to estrogen, daily progesterone injections for three weeks elevated CSD susceptibility, and one-week withdrawal after two weeks of treatment partially normalized this effect. Autoradiography did not reveal significant changes in glutamate or GABAA receptor binding density after estrogen treatment and withdrawal. Conclusions: These data suggest that females are more susceptible to CSD, and sexual dimorphism is abrogated by gonadectomy. Moreover, estrogen withdrawal after prolonged daily treatment enhances CSD susceptibility. These findings may have implications for estrogen-withdrawal migraine, although the latter tends to be without aura. [ABSTRACT FROM AUTHOR]

In humans, estrogens are considered protective factor against atherosclerosis because the risk increases in postmenopausal women. However, it is not clear whether estrogens are the only factor, whether sex chromosomes also have an influence, and whether estrogens play the same role in all mammals. The mouse line C57BL/6J is prone to develop atherosclerotic changes in the largest arteries after prolonged feeding of a highfat diet containing cholesterol and cholate (Paigen diet). We aimed to examine effect of sex hormones and sex chromosome complement on the development of atherosclerotic plaques using agonadal SF-1 knockout mouse on C57BL/6J background. Gonadally intact and prepubertally gonadectomized WT and agonadal SF-1 knockout C57BL/6J mice of both sexes were exposed to a Paigen diet and a control diet for 20 weeks. We monitored their body weight, food intake, and serum lipid profile. The aortas were examined by the en face method, and the cross sections of the aortic bulbs were stained for lipid content. In all groups of mice, atherosclerotic changes were small and confined to the aortic bulb. The formation of atherosclerotic plaques was sex- and hormone-dependent, as female animals with functioning ovaries developed the most prominent atherosclerotic plaques. Gonadally intact females were also the only group that gained weight comparably on control or atherogenic diet. Diet affected blood biochemistry, but there were almost no significant differences between groups in serum lipid levels. Results indicated main mechanism causing sex-dependent differences in atherosclerosis depends on sex hormones rather than sex chromosomes. Our results also suggest that a mouse model of dietary induced atherosclerosis is of limited use to study the mechanisms of atherosclerosis in humans because the presence of estrogens impairs lipid metabolism and contributes to the formation of atherosclerotic plaques. [ABSTRACT FROM AUTHOR]

Evolution of genetic mechanisms of sex determination led to two processes causing sex differences in somatic phenotypes: gonadal differentiation and sex chromosome dosage inequality. In species with heteromorphic sex chromosomes, the sex of the individual is established at the time of formation of the zygote, leading to inherent sex differences in expression of sex chromosome genes beginning as soon as the embryonic transcriptome is activated. The inequality of sex chromosome gene expression causes sexual differentiation of the gonads and of non-gonadal tissues. The difference in gonad type in turn causes lifelong differences in gonadal hormones, which interact with unequal effects of X and Y genes acting within cells. Separating the effects of gonadal hormones and sex chromosomes has been possible using mouse models in which gonadal determination is separated from the sex chromosomes, allowing comparison of XX and XY mice with the same type of gonad. Sex differences caused by gonadal hormones and sex chromosomes affect basic physiology and disease mechanisms in most or all tissues.

Visceral pain and stress are tightly intertwined bodily and emotional phenomena, which enable a flexible adaptation to environmental challenges by activating a response repertoire to restore homeostasis along the gut-brain axis. However, visceral pain and stress can persist widely independent of the initial cause, acquiring independent disease values and posing major health burdens as predominant features in disorders of gut-brain interaction (DGBI). Epidemiological data consistently documents an increased prevalence for women to suffer from chronic visceral pain, possibly shaped by sex hormones and modulated by stress and its biological and psychosocial correlates. Yet, mechanisms underlying the complex interactions between altered visceroception, stress and sex remain widely elusive, especially in clinical populations with DGBI.We herein selectively review mechanisms of interactions between stress and sex in the complex pathophysiology of DGBI. A particular emphasis is laid on visceral pain, in which stress constitutes a major risk factor as well as mediator, and sex-related differences are particularly pronounced. Building on the neurobiology of stress and mechanisms of gut-brain interactions, we highlight putative target mechanisms via which visceral pain and stress may converge with sex effects into a triad.Accommodating a global demographic shift, we propose a lifespan perspective in future research, which may enable a more fine-tuned evaluation of this complex interplay exerting distinct challenges during vulnerable developmental phases. This viewpoint may advance our understanding of pathophysiological processes and can ultimately inspire novel tailored prevention strategies and therapeutic approaches in the treatment of chronic visceral pain and DGBI across the lifespan.

In humans, estrogens are considered protective factor against atherosclerosis because the risk increases in postmenopausal women. However, it is not clear whether estrogens are the only factor, whether sex chromosomes also have an influence, and whether estrogens play the same role in all mammals. The mouse line C57BL/6J is prone to develop atherosclerotic changes in the largest arteries after prolonged feeding of a high-fat diet containing cholesterol and cholate (Paigen diet). We aimed to examine effect of sex hormones and sex chromosome complement on the development of atherosclerotic plaques using agonadal SF-1 knockout mouse on C57BL/6J background. Gonadally intact and prepubertally gonadectomized WT and agonadal SF-1 knockout C57BL/6J mice of both sexes were exposed to a Paigen diet and a control diet for 20 weeks. We monitored their body weight, food intake, and serum lipid profile. The aortas were examined by the en face method, and the cross sections of the aortic bulbs were stained for lipid content. In all groups of mice, atherosclerotic changes were small and confined to the aortic bulb. The formation of atherosclerotic plaques was sex- and hormone-dependent, as female animals with functioning ovaries developed the most prominent atherosclerotic plaques. Gonadally intact females were also the only group that gained weight comparably on control or atherogenic diet. Diet affected blood biochemistry, but there were almost no significant differences between groups in serum lipid levels. Results indicated main mechanism causing sex-dependent differences in atherosclerosis depends on sex hormones rather than sex chromosomes. Our results also suggest that a mouse model of dietary induced atherosclerosis is of limited use to study the mechanisms of atherosclerosis in humans because the presence of estrogens impairs lipid metabolism and contributes to the formation of atherosclerotic plaques. ŽENSKI SPOLNI HORMONI PREDSTAVLJAJO DEJAVNIK TVEGANJA ZA NASTANEK ATEROSKLEROZNIH SPREMEMB PRI MIŠIH LINIJE C57BL/6J NA ATEROGENI DIETI Izvleček: Pri ženskah se v postmenopavznem obdobju poveča tveganje za razvoj ateroskleroze, zato je splošno sprejeto, da estrogeni hormoni varujejo ožilje pred razvojem tega žilnega obolenja. Ni pa še popolnoma raziskano, ali so estrogeni poglavitni dejavnik, ali imajo vpliv tudi spolni kromosomi in ali je vpliv spolnih hormonov enak med sesalci. Živalski modeli za proučevanje ateroskleroznega obolenja so redki, eden izmed njih so miši linije C57BL/6J, ki lahko spontano razvijejo aterosklerotične spremembe v večjih telesnih arterijah, če se jih dlje časa hrani s hrano z visoko vsebnostjo maščob, z dodatkom holesterola in holata - s t.i. aterogeno dieto po Paigenu. V raziskavi smo želeli proučiti vpliv spolnih hormonov in spolnih kromosomov na razvoj aterosklerotičnih plakov v žilah s pomočjo modela miši z izbitim genom SF-1, ki se razvijejo brez spolnih organov. 20 tednov smo mišim dajali hrano po receptu Paigen oziroma kontrolno hrano z nižjo vsebnostjo maščob. Miši obeh spolov so bile bodisi brez spolnih organov zaradi izbitega gena SF-1 (na ozadju C57BL/6J), bodisi smo jim gonade operativno odstranili pred puberteto. Tretjino samcev in samic smo pustili intaktne z gonadami. Spremljali smo telesno težo živali, povprečno porabo hrane in opravili analizo serumskih lipidov. Pregledali smo preparirane aorte po metodi en-face ter ocenili obseg plakov in maščob na prečnih rezih aortnega korena na nivoju aortnih zaklopk s histološkim barvanjem in analizo mikroskopske slike. Pri vseh skupinah miši, ki so bile hranjene z aterogeno dieto, so bile aterosklerotične spremembe relativno majhne in omejene na aortni koren. Obseg plakov je bil odvisen od kromosomskega spola in prisotnosti hormonov, plaki so bili najbolj očitni pri samicah z jajčniki. Istočasno so bile intaktne samice edina skupina živali, ki so podobno pridobivale na teži tako na aterogeni kot kontrolni hrani, pri ostalih skupinah so živali na aterogeni dieti priraščale bistveno manj. Vrsta hrane je imela vpliv na serumski lipidni profil, vendar praktično ni bilo statistično značilnih razlik med različnimi skupinami živali in analize krvnega seruma nismo mogli povezati z drugimi ugotovljenimi odstopanji pri samicah. Rezultati raziskave kažejo, da so glavni povod za spolne razlike pri razvoju aterosklerotičnih sprememb spolni hormoni in ne spolni kromosom. Hkrati pa rezultati postavljajo pod vprašaj uporabnost mišjih modelov za proučevanje ateroskleroze, ki jo induciramo s prehrano, saj prisotnost estrogenov – obratno kot pri ljudeh - pri miših negativno vpliva na presnovo lipidov in doprinese k izoblikovanju aterosklerotičnih plakov. Ključne besede: ateroskleroza; dieta po Paigenu; spol; spolni hormoni; miš, lipidi in holesterol

Circadian disruption (CD) is the consequence of a mismatch between endogenous circadian rhythms and behavior, and frequently occurs in shift workers. CD has often been linked to impairment of glucose and lipid homeostasis. It is, however, unknown if these effects are sex dependent. Here, we subjected male and female C57BL/6J mice to 6-h light phase advancements every 3 days to induce CD and assessed glucose and lipid homeostasis. Within this model, we studied the involvement of gonadal sex hormones by injecting mice with gonadotropin-releasing hormone-antagonist degarelix. We demonstrate that CD has sex-specific effects on glucose homeostasis, as CD elevated fasting insulin levels in male mice while increasing fasting glucose levels in female mice, which appeared to be independent of behavior, food intake, and energy expenditure. Absence of gonadal sex hormones lowered plasma insulin levels in male mice subjected to CD while it delayed glucose clearance in female mice subjected to CD. CD elevated plasma triglyceride (TG) levels and delayed plasma clearance of TG-rich lipoproteins in both sexes, coinciding with reduced TG-derived FA uptake by adipose tissues. Absence of gonadal sex hormones did not notably alter the effects of CD on lipid metabolism. We conclude that CD causes sex-dependent effects on glucose metabolism, as aggravated by male gonadal sex hormones and partly rescued by female gonadal sex hormones. Future studies on CD should consider the inclusion of both sexes, which may eventually contribute to personalized advice for shift workers. [ABSTRACT FROM AUTHOR]

Fibromyalgia (FM) is a chronic pain disorder with unclear pathophysiological mechanisms, which leads to challenges in patient management. In addition to pain, the disorder presents with a broad range of symptoms, such as sleep disruption, chronic fatigue, brain fog, depression, muscle stiffness, and migraine. FM has a considerable female prevalence, and it has been shown that symptoms are influenced by the menstrual cycle and periods of significant hormonal and immunological changes. There is increasing evidence that females with FM experience an aggravation of symptoms in pregnancy, particularly during the third trimester and after childbirth. In this perspective paper, we focus on the neuro-endocrine interactions that occur between progesterone, allopregnanolone, and cortisol during pregnancy, and propose that they align with our previously proposed model of FM pathogenesis based on GABAergic "weakening" in a thalamocortical neural loop system. Based on our hypothesis, we introduce the possibility of utilizing transcranial direct current stimulation (tDCS) as a non-invasive treatment potentially capable of exerting sex-specific effects on FM patients. [ABSTRACT FROM AUTHOR]

Circadian rhythms provide daily temporal structure to cellular and organismal biological processes, ranging from gene expression to cognition. Higher-frequency (intradaily) ultradian rhythms are similarly ubiquitous but have garnered far less empirical study, in part because of the properties that define them—multimodal periods, non-stationarity, circadian harmonics, and diurnal modulation–pose challenges to their accurate and precise quantification. Wavelet analyses are ideally suited to address these challenges, but wavelet-based measurement of ultradian rhythms has remained largely idiographic. Here, we describe novel analytical approaches, based on discrete and continuous wavelet transforms, which permit quantification of rhythmic power distribution across a broad ultradian spectrum, as well as precise identification of period within empirically determined ultradian bands. Moreover, the aggregation of normalized wavelet matrices allows group-level analyses of experimental treatments, thereby circumventing limitations of idiographic approaches. The accuracy and precision of these wavelet analyses were validated using in silico and in vivo models with known ultradian features. Experiments in male and female mice yielded robust and repeatable measures of ultradian period and power in home cage locomotor activity, confirming and extending reports of ultradian rhythm modulation by sex, gonadal hormones, and circadian entrainment. Seasonal changes in day length modulated ultradian period and power, and exerted opposite effects in the light and dark phases of the 24 h day, underscoring the importance of evaluating ultradian rhythms with attention to circadian phase. Sex differences in ultradian rhythms were more prominent at night and depended on gonadal hormones in male mice. Thus, relatively straightforward modifications to the wavelet procedure allowed quantification of ultradian rhythms with appropriate time-frequency resolution, generating accurate, and repeatable measures of period and power which are suitable for group-level analyses. These analytical tools may afford deeper understanding of how ultradian rhythms are generated and respond to interoceptive and exteroceptive cues. [ABSTRACT FROM AUTHOR]